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METTL1-mediated m⁷G modification of Arg-TCT tRNA drives oncogenic transformation.

ABSTRACT: The emerging "epitranscriptomics" field is providing insights into the biological and pathological roles of different RNA modifications. The RNA methyltransferase METTL1 catalyzes N7-methylguanosine (m⁷G) modification of tRNAs. Here we find METTL1 is frequently amplified and overexpressed in cancers and is associated with poor patient survival. METTL1 depletion causes decreased abundance of m⁷G-modified tRNAs and altered cell cycle and inhibits oncogenicity. Conversely, METTL1 overexpression induces oncogenic cell transformation and cancer. Mechanistically, we find increased abundance of m⁷G-modified tRNAs, in particular Arg-TCT-4-1, and increased translation of mRNAs, including cell cycle regulators that are enriched in the corresponding AGA codon. Accordingly, Arg-TCT expression is elevated in many tumor types and is associated with patient survival, and strikingly, overexpression of this individual tRNA induces oncogenic transformation. Thus, METTL1-mediated tRNA modification drives oncogenic transformation through a remodeling of the mRNA "translatome" to increase expression of growth-promoting proteins and represents a promising anti-cancer target.

SUBMITTER: Orellana EA

PROVIDER: S-EPMC8380730 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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METTL1-mediated m7G modification of Arg-TCT tRNA drives oncogenic transformation.

Orellana Esteban A EA Liu Qi Q Yankova Eliza E Pirouz Mehdi M De Braekeleer Etienne E Zhang Wencai W Lim Jihoon J Aspris Demetrios D Sendinc Erdem E Garyfallos Dimitrios A DA Gu Muxin M Ali Raja R Gutierrez Alejandro A Mikutis Sigitas S Bernardes Gonçalo J L GJL Fischer Eric S ES Bradley Allan A Vassiliou George S GS Slack Frank J FJ Tzelepis Konstantinos K Gregory Richard I RI

Molecular cell 20210804 16

The emerging "epitranscriptomics" field is providing insights into the biological and pathological roles of different RNA modifications. The RNA methyltransferase METTL1 catalyzes N7-methylguanosine (m7G) modification of tRNAs. Here we find METTL1 is frequently amplified and overexpressed in cancers and is associated with poor patient survival. METTL1 depletion causes decreased abundance of m7G-modified tRNAs and altered cell cycle and inhibits oncogenicity. Conversely, MET ...[more]

PMID: 34352207

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Project description:BackgroundNeuroblastoma (NBL) is the most common extra-cranial solid tumour in childhood, with prognosis ranging from spontaneous remission to high risk for rapid and fatal progression. Despite existing therapy approaches, the 5-year event-free survival (EFS) for patients with advanced NBL remains below 30%, emphasizing urgent necessary for novel therapeutic strategies. Studies have shown that epigenetic disorders play an essential role in the pathogenesis of NBL. However, the function and mechanism of N7-methylguanosine (m7G) methyltransferase in NBL remains unknown.MethodsThe expression levels of m7G tRNA methyltransferase Methyltransferase-like 1 (METTL1) were analyzed by querying the Gene Expression Omnibus (GEO) database and further confirmed by immunohistochemistry (IHC) assay. Kaplan-Meier, univariate and multivariate cox hazard analysis were performed to reveal the prognostic role of METTL1. Cell function assays were performed to evaluate how METTL1 works in proliferation, apoptosis and migration in cell lines and xenograft mouse models. The role of METTL1 on mRNA translation activity of NBL cells was measured using puromycin intake assay and polysome profiling assay. The m7G modified tRNAs were identified by tRNA reduction and cleavage sequencing (TRAC-seq). Ribosome nascent-chain complex-bound mRNA sequencing (RNC-seq) was utilized to identify the variation of gene translation efficiency (TE). Analyzed the codon frequency decoded by m7G tRNA to clarify the translation regulation and mechanism of m7G modification in NBL.ResultsThis study found that METTL1 were significantly up-regulated in advanced NBL, which acted as an independent risk factor and predicted poor prognosis. Further in NBL cell lines and BALB/c-nu female mice, we found METTL1 played a crucial role in promoting NBL progression. Furthermore, m7G profiling and translation analysis revealed downregulation of METTL1 would inhibit puromycin intake efficiency of NBL cells, indicating that METTL1 did count crucially in regulation of NBL cell translation. With all tRNAs with m7G modification identified in NBL cells, knockdown of METTL1 would significantly reduce the levels of both m7G modification and m7G tRNAs expressions. Result of RNC-seq shew there were 339 overlapped genes with impaired translation in NBL cells upon METTL1 knockdown. Further analysis revealed these genes contained higher frequency of codons decoded by m7G-modified tRNAs and were enriched in oncogenic pathways.ConclusionThis study revealed the critical role and mechanism of METTL1-mediated tRNA m7G modification in regulating NBL progression, providing new insights for developing therapeutic approaches for NBL patients.

Project description:BackgroundCancer cells selectively promote the translation of oncogenic transcripts to stimulate cancer progression. Although growing evidence has revealed that tRNA modifications and related genes participate in this process, their roles in head and neck squamous cell carcinoma (HNSCC) remain largely uncharacterized. Here, we sought to investigate the function and mechanisms of the transfer RNA (tRNA) N7-methylguanosine (m7 G) modification in regulating the occurrence and development of HNSCC.MethodsCell lost-of-function and gain-of-function assays, xenograft models, conditional knockout and knockin mouse models were used to study the physiological functions of tRNA m7 G modification in HNSCC tumorigenesis. tRNA modification and expression profiling, mRNA translation profiling and rescue assays were performed to uncover the underlying molecular mechanisms. Single-cell RNA sequencing (scRNA-seq) was conducted to explore the tumor microenvironment changes.ResultsThe tRNA m7 G methyltransferase complex components Methyltransferase-like 1 (METTL1)/WD repeat domain 4 (WDR4) were upregulated in HNSCC and associated with a poor prognosis. Functionally, METTL1/WDR4 promoted HNSCC progression and metastasis in cell-based and transgenic mouse models. Mechanistically, ablation of METTL1 reduced the m7 G levels of 16 tRNAs, inhibiting the translation of a subset of oncogenic transcripts, including genes related to the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. In addition, chemical modulators of the PI3K/Akt/mTOR signaling pathway reversed the effects of Mettl1 in mouse HNSCC. Furthermore, scRNA-seq results revealed that Mettl1 knockout in mouse tumor cells altered the immune landscape and cell-cell interaction between the tumor and stromal compartment.ConclusionsThe tRNA m7 G methyltransferase METTL1 was found to promote the development and malignancy of HNSCC through regulating global mRNA translation, including the PI3K/AKT/mTOR signaling pathway, and found to alter immune landscape. METTL1 could be a promising treatment target for HNSCC patients.

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METTL1-mediated m⁷G modification of Arg-TCT tRNA drives oncogenic transformation.

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METTL1-mediated m<sup>7</sup>G modification of Arg-TCT tRNA drives oncogenic transformation.

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METTL1-mediated m7G modification of Arg-TCT tRNA drives oncogenic transformation.

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METTL1-mediated m&lt;sup&gt;7&lt;/sup&gt;G modification of Arg-TCT tRNA drives oncogenic transformation.

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METTL1-mediated m⁷G modification of Arg-TCT tRNA drives oncogenic transformation.

METTL1-mediated m<sup>7</sup>G modification of Arg-TCT tRNA drives oncogenic transformation.